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Alpha-1 Antitrypsin Therapy Modulates the Neutrophil Membrane Proteome and Secretome

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Alpha-1 Antitrypsin Therapy Modulates the Neutrophil Membrane Proteome and Secretome Early View Original article Alpha-1 antitrypsin therapy modulates the neutrophil membrane proteome and secretome Mark P. Murphy, Thomas McEnery, Karen McQuillan, Oisín F. McElvaney, Oliver J. McElvaney, Sarah Landers, Orla Coleman, Anchalin Bussayajirapong, Padraig Hawkins, Michael Henry, Paula Meleady, Emer P. Reeves, Noel G. McElvaney Please cite this article as: Murphy MP, McEnery T, McQuillan K, et al. Alpha-1 antitrypsin therapy modulates the neutrophil membrane proteome and secretome. Eur Respir J 2020; in press (https://doi.org/10.1183/13993003.01678-2019). This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Copyright ©ERS 2020 Alpha-1 antitrypsin therapy modulates the neutrophil membrane proteome and secretome Mark P. Murphy,1 Thomas McEnery,1 Karen McQuillan,1 Oisín F. McElvaney,1 Oliver J. McElvaney,1 Sarah Landers,1 Orla Coleman,2 Anchalin Bussayajirapong,1 Padraig Hawkins,1 Michael Henry,2 Paula Meleady,2 Emer P. Reeves,1 Noel G. McElvaney1 1 Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland. 2 National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland. Correspondence should be addressed to: Dr Emer P. Reeves, Ph.D., Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland. [email protected], +35318093877 Authorship note: Noel G. McElvaney and Emer P. Reeves share joint senior authorship. Conflict of interest statement: The authors have declared that no conflict of interest exists Take home message: Neutrophils from patients with COPD due to alpha-1 antitrypsin deficiency illustrate an altered membrane protein profile and primary granule exocytosis pattern compared to cells from COPD patients without AATD, a defect corrected by augmentation therapy Abstract Obstructive pulmonary disease in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) occurs earlier in life compared to patients without AATD. To understand this further, the aim of this study was to investigate whether AATD presents with altered neutrophil characteristics, due to the specific lack of plasma AAT, compared to non-AATD COPD. This study focused on the neutrophil plasma membrane, and by use of label-free tandem mass spectrometry, the proteome of the neutrophil membrane was compared in FEV1-matched AATD, non-AATD COPD and in AATD patients receiving weekly AAT augmentation therapy (n=6 patients per cohort). Altered protein expression in AATD was confirmed by western blot, ELISA and fluorescence resonance energy transfer analysis. The neutrophil membrane proteome in AATD differed significantly from that of COPD as demonstrated by increased abundance and activity of primary granule proteins including neutrophil elastase on the cell surface in AATD. The signalling mechanism underlying increased degranulation involved Rac2 activation, subsequently resulting in proteinase-activated receptor 2 activation by serine proteinases and enhanced reactive oxygen species production. In vitro and ex vivo, AAT reduced primary granule release and the described plasma membrane variance was resolved post AAT augmentation therapy in vivo, the effects of which significantly altered the AATD neutrophil membrane proteome to that of a non-AATD COPD cell. These results provide strong insight into the mechanism of neutrophil driven airways disease associated with AATD. Therapeutic AAT augmentation modified the membrane proteome to that of a typical COPD cell, with implications for clinical practice. Introduction Alpha-1 antitrypsin (AAT) is recognised as a potent inhibitor of serine proteinases, primarily neutrophil elastase (NE) [1]. AAT is produced mainly by hepatocytes and is released into the circulation yielding a plasma concentration of approximately 1.5g/L. Alpha-1 antitrypsin deficiency (AATD) gives rise to reduced levels of AAT and is a genetic risk factor for the development of chronic obstructive pulmonary disease (COPD). Emphysema, routinely characterised by computed tomography (CT) [2], is an important feature of AATD, classically panacinar in nature, in contrast to the mainly centrilobular disease seen in non-AATD COPD. AAT augmentation therapy, which involves intravenous infusion of plasma purified human AAT, demonstrated a reduced rate of lung density loss [3, 4]. Moreover, improved biochemical effects of double AAT dosing (120 mg/kg/week) in AATD was recently described [5]. Although lung disease in AATD patients typically starts at an earlier stage in life compared to patients with COPD without AATD, wide-ranging studies have been performed to discriminate between AATD and non-AATD COPD phenotypes. Such studies include evaluating complications and survival post lung transplant [6], plasma and urine biomarkers [7, 8], pulmonary rehabilitation [2], quality of life [9] and differences in adjusting to illness [10]. Airway neutrophilia is a feature of COPD with and without AATD, with increased neutrophil numbers reported in epithelial lining fluid of non- smoking AATD individuals compared to healthy controls, and are implicated in many of the pathological features associated with the disease, including unopposed neutrophil elastolytic activity [11]. In addition, airway neutrophilia has been described in AATD subjects even with mild functional lung impairment [12]. A possible explanation for increased neutrophil responsiveness in AATD is put forward by studies demonstrating that AAT possesses key anti-inflammatory properties independent of anti-protease activity. This is particularly relevant in regards to modifying essential neutrophil functions including leukotriene B4 induced adhesion [13], chemotaxis in response to interleukin-8 [14], degranulation of secondary and tertiary granules via tumour necrosis factor-alpha (TNF)-signalling [15], oxidative activation [16] and the ability of AAT to normalize proapoptotic signals in circulating neutrophils [17]. It has previously been shown that AAT binds neutrophil plasma membranes, localised to membrane lipid rafts [14]. This raised the question of whether AAT augmentation therapy in AATD- COPD patients could bind the circulating AATD cell in vivo and modify the AATD neutrophil to that of a non-AATD COPD type cell. For this analysis, we chose to examine the neutrophil plasma membrane, which represents the interface between the cell and its environment and in large part determines a cell’s response to stimuli. The aim of this study was to perform the first proteomic analysis of plasma membranes of neutrophils from AATD-COPD compared to non-AATD COPD individuals, and to elucidate the impact of AAT augmentation therapy. Finally, our objective was to identify the consequence of altered membrane protein expression on neutrophil function. Materials and methods Study design Ethical approval from Beaumont Hospital Institutional Review Board was acquired and written informed consent obtained from all study participants (approval number 18/52). Healthy control volunteers (table 1) showed no evidence of any disease and had no respiratory symptoms; none were taking medication, all non-smokers and all proven MM phenotype with serum AAT concentrations within the normal range (1.5gL). AATD patients (homozygous for the Z-allele, non-smokers) were recruited from the Irish Alpha-1 Antitrypsin Deficiency Registry (table 1) and were classified as healthy AATD individuals (FEV1>80% predicted), AATD individuals with airway obstruction (FEV1 < 80% predicted with obstructive pattern on spirometry (i.e. FEV1/FVC ratio <0.7) and emphysema on CT), or AATD patients on augmentation therapy receiving plasma purified AAT from CSL Behring (Zemaira®) administered intravenously at a dosage of 60mg/kg body weight weekly. Non-smoking COPD patients (FEV1<80% predicted, with obstructive pattern i.e. FEV1/FVC ratio <0.7 and emphysema on CT) with serum AAT concentrations within the normal range were recruited from Beaumont Hospital (table 1). In the six weeks prior to obtaining blood samples, all patients were exacerbation free. Neutrophil isolation and cell assays. The methods for blood sampling for plasma and neutrophil isolation, along with plasma membrane isolation, quantitative label-free LC-MS/MS, Western blot analyses and ELISA are outlined in the Supplementary Materials and Methods. Fluorescence resonance energy transfer (FRET) analysis [18] and cytochrome c reduction assays [19] are described in detail in the Supplementary Materials and Methods section. Statistical analysis Results are expressed as mean ± SEM of biological replicates or independent experiments as stated in each figure legend. Data analysis was performed using GraphPad PRISM 8.0 (San Diego, USA). Students’ paired t-test was used where distribution was normal and when comparisons were being made between two matched groups. One-way or two-way ANOVA was used for independent group comparisons, followed post-hoc by Tukeys’ multiple comparison test where appropriate. Non-parametric Wilcoxon signed rank testing was employed where data were not normal (by Shapiro-Wilk test). Results were considered significant when p<0.05. Proteomics
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